Azacycloalkane derivatives are compounds which are useful as absorption promoters capable of enhancing the penetrability and permeability of drugs while scarcely irritating biomembranes and having little systemic toxicity. Among these compounds, 1-[2-(decylthio)ethyl]azacyclopentan-2-one exerts remarkable effects and, therefore, is expected as highly useful in medicines and agricultural chemicals.
As will be described hereinafter, however, the existing process for producing 1-[2-(decylthio)ethyl]azacyclopentan-2-one with such a high purity as to be applicable to medicines and agricultural chemicals are far from satisfactory from the industrial and economic viewpoints. Therefore, it has been urgently required to develop a process for readily producing such compound at a low cost.
More specifically, the existing processes for producing azacycloalkane derivatives include the following ones, as described in Japanese Patent Application Laid-Open Gazette No. Sho. 62-238261 (238261/1987):
(1) a process comprising reacting an azacycloalkan-2-one with a dihalogenoalkyl in excess in the presence of an alkali metal hydride catalyst to obtain a reaction product and then reacting the product with a halogenoalkyl in the presence of a phase transfer catalyst in an alkaline aqueous solution of sodium sulfide; PA1 (2) a process comprising adding a dihalogenoalkyl in large excess to an azacycloalkan-2-one in the presence of an alkali metal hydride catalyst to obtain a reaction product and then reacting the product with an alkyl mercaptan in the presence of a dehydrohalogenating agent in an inert solvent which does not participate in the reaction; PA1 (3) a process comprising reacting a 1-(n-alkenyl)azacycloalkan-2-one with an alkyl mercaptan in the presence of a radical initiator in benzene or the like; PA1 (4) a process comprising reacting an alkyl mercaptan with a dihalogenoalkyl in excess in the presence of a dehydrohalogenating agent to obtain a reaction product and then reacting the product with an azacycloalkan-2-one; and PA1 (5) a process comprising adding a halogenoalkyl mercaptan to an alkali salt of an azacycloalkan-2-one to obtain a reaction product and then reacting the product with a halogenoalkyl in the presence of a dehydrohalogenating agent. PA1 R represents an alkyl group having 3 to 12 carbon atoms,
However, each of these processes has some serious industrial problems and, therefore, is not satisfactory.
In the above processes (1), (2), (4) and (5), for example, it is necessary to use an alkali metal hydride which is expensive and difficult to handle. In addition, the reaction time is as long as about 12 hours and a product with a high purity can be hardly obtained. Therefore, much labor is required for purifying the product. Thus, these processes cannot be regarded as industrially advantageous ones. Furthermore, it requires a long time and a large cost to secure a high purity by these processes.
On the other hand, the above process (3) is a relatively easy one. However, a considerably large amount of dialkyl disulfides having boiling points closely similar to those of azacycloalkane derivatives are formed as by-products in this case. Accordingly, a product of such a high purity as to be applicable to medicines and agricultural chemicals can be hardly obtained by simple procedures such as distillation (see Comparative Example 1 which will be given hereinafter). In order to remove these by-products, it is necessary to perform troublesome operations such as column chromatography or recrystallization prior to distillation. Thus, this process cannot be regarded as an economically advantageous one. Further, it has been confirmed that the use of benzene or the like as the reaction solvent causes the formation of isomers which lowers the purity of the product, since it is impossible to completely remove these isomers by column chromatography, recrystallization or distillation.
An object of the present invention is to solve these problems encountered in the prior art and more particularly it is to provide an industrially advantageous process for producing an azacycloalkane derivative whereby the desired compound with a high purity can be easily obtained and good economical and operation characteristics can be achieved.